A major research emphasis in the last year has been to utilize the behavior genetics method and a classical pharmacological approach to determine genetic and pharmacological contributions to characteristics important in the acute effects of opioids and opioid receptor regulation. As an example, autoradiographic data from transgenic mice carrying the human Cu/Zn-superoxide dismutase gene demonstrate an increase in mu-opioid receptor concentration in dopaminergic-related areas and the central gray area. The relative potencies of mu-, d- and k-opioid receptor agonists to induce antinociception in heterozygous and homozygous superoxide dismutase transgenic mice as well as four inbred strains was assessed to determine the functional significance of the increased receptor concentration. Increased superoxide dismutase activity resulted in an increased sensitivity to mu-agonists in a gene dosage-dependent manner. SOD/Tg/hom mice were less sensitive to the d opioid-agonist than were SOD/Tg/het mice. The superoxide dismutase transgene did not affect k opioid receptor agonist sensitivity. These data suggest that d-opioid receptors are not regulated in the same manner as mu-opioid receptors and that k-opioid receptors are unaffected by superoxide dismutase activity. In related series of studies, the investigation of genetic differences in d opioid subtypes and descending neural control of supraspinal analgesia have revealed intricate interactions between the mechanism by which d opioid agonists produce analgesia suprasinally and how it is mediated spinally. Supra-spinally administered d opioid agonists can produce analgesia via mu or d mechanisms that are mediated spinally via GABAA, GABAB, or 5HT mechanisms. In addition, the volatile anesthetic isoflurane has been found to antagonize (perhaps through a spinal mechanism) d opioid agonist induced analgesia.